Anesthesia-triggered dopaminergic bursts actively induce forgetting: a paradigm shift in understanding cold-shock amnesia

Abstract Retrograde memory loss, the inability to recall events preceding amnesia onset, is a well-documented consequence of anesthesia. Recent discoveries, pioneered by Drosophila research, have challenged the view that forgetting is a passive process, and have demonstrated that rather it is a highly active, well-regulated biological process. This work builds on this and makes a remarkable and unexpected discovery that anesthesia itself triggers a robust, widespread burst of activity in dopaminergic neurons. Here, we report that both cold-shock and CO2 anesthesia elicits strong activation in PAM and PPL1 dopaminergic neuron populations. This calcium activity is accompanied by robust synaptic release of dopamine. Strikingly, pharmacological experiments show that this response is input-driven, as it is completely abolished by Na+ channel blockers and dampened by nAChR antagonists. Using behavioral methods, crucially, we show that anesthesia-induced amnesia can be prevented by blocking activity in PAM and PPL1 neurons during anesthesia. Together, our findings reveal a previously unrecognized active mechanism by which anesthesia induces forgetting, mediated by rapid dopaminergic signaling. This paradigm-shifting discovery redefines how we think about anesthesia-induced amnesia and the biology of forgetting. Competing Interest Statement The authors have declared no competing interest. Footnotes This version of the manuscript now includes all supplemental data/figures.